Vascular health declines with aging, and the decline is associated with peripheral artery disease. The long- term goal of this proposal is to understand the link between exercise, histamine receptors, and alterations in endothelial and vascular function so that we can exploit this link to generate novel interventions to improve or maintain vascular health in aging and treat patients with peripheral artery disease. In this context, a single bout of exercise is followed by a sustained peripheral vasodilation of the previously active skeletal muscle (sustained post exercise vasodilation). Histamine H1 and H2-receptors are the primary cause of sustained post exercise vasodilation. We speculate that this histaminergic pathway may play a role in improving endothelial function and stimulating vascular remodeling in response to exercise. It is unknown what signals associated with exercise activate this histaminergic pathway, or whether histamine released from mast cells or de novo production of histamine is responsible for activation of H1 and H2-receptors following exercise. It is unknown what signals related to endothelial function and vascular remodeling are dependent on activation of these receptors. Lastly, it is unclear whether the histaminergic pathway remains responsive to exercise or other stimuli in older subjects. We propose the following specific aims: 1) Identify the exercise-related signal that activates this histaminergic pathway, 2) Determine the source of histamine released by this signal, 3) Determine key endothelial and vascular regulatory signals that respond to activation of this pathway, and 4) Determine responsiveness of this pathway to exercise in older men and women. These aims are supported by the PI's prior work and will be addressed using state-of-the-art techniques in humans. Information from these studies will prove valuable on five fronts. First, these studies will expand current understanding of the vascular changes that occur following exercise. Second, we expect these studies will prove that histamine, generally associated with pathophysiological responses (e.g., asthma, allergies, anaphylaxis, and tumor growth), can play important roles in day-to-day regulation of regional blood flow related to exercise. Third, we expect these studies will identify a key pathway that contributes to the cardiovascular health benefits of lifetime physical activity by modulating critical signals for endothelial and vascular health. Fourth, we expect to show this pathway is functional in older men and women. Last, we expect these studies will identify a mechanism that can be exploited by future interventions to protect the vasculature from the age-associated decline in endothelial and vascular health and to treat peripheral artery disease. In summary, these studies will contribute to the understanding of exercise as a therapeutic modality in treatment and prevention of cardiovascular disease and set the stage for new vascular health interventions targeted at older individuals, in particular, those with conditions such as peripheral artery disease.